Synthesis of a compound that modulates kinases

ABSTRACT

The present disclosure provides processes for the preparation of a compound of formula I: 
                         
or a salt thereof, active on the receptor protein kinases c-Kit and/or c-Fms and/or Flt3. The disclosure also provides compounds and processes for the preparation of the compounds that are synthetic intermediates to the compound of formula I.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.15/665,804, filed Aug. 1, 2017, now U.S. Pat. No. 10,040,792, which is adivisional of U.S. application Ser. No. 15/147,709, filed May 5, 2016,now U.S. Pat. No. 9,745,298, which application claims the benefit under35 U.S.C. § 119(e) to U.S. Provisional Application No. 62/157,902, filedMay 6, 2015, and U.S. Provisional Application No. 62/241,040, filed Oct.13, 2015, each of which is incorporated herein by reference in itsentirety.

FIELD

The present disclosure relates generally to the field of organicsynthetic methodology for the preparation of compounds modulatingkinases and their synthetic intermediates.

BACKGROUND

The compound named,[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine,which is also known as pexidartinib, is effective for treating subjectssuffering from or at risk of a c-Kit and/or c-Fms and/or Flt3 mediateddisease or condition. Suitable compounds, including pexidartinib or asalt thereof, for the treatment of such diseases and conditions aredisclosed in U.S. Pat. No. 7,893,075, U.S. Publication No. 2014-0037617and U.S. Publication No. 2013-0274259, the disclosures of all of whichare incorporated herein by reference in their entirety.

There remains a need in developing new versatile and facile processesfor the efficient preparation of pexidartinib and other similarmolecules, especially in an industrial scale.

SUMMARY

The present disclosure provides in one embodiment a process for making acompound of formula I, named[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine:

or a salt thereof.

In another embodiment, this disclosure provides a process for making acompound of formula II, named[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amineHCl salt:

In another embodiment, this disclosure provides a process forpreparation of a compound of formula III:

or a salt thereof;comprising contacting a compound of formula A or a salt thereof, with acompound of formula B or a salt thereof:

under addition conditions to provide the compound of formula III or asalt thereof, wherein each PG independently is a protecting group.

In another embodiment, this disclosure provides a process forpreparation of a compound of formula IV:

or a salt thereof;comprising subjecting a compound of formula III:

or a salt thereof, to N-deprotection and alcohol reduction conditions toprovide the compound of formula IV or a salt thereof, wherein each PGindependently is a protecting group. In another embodiment, thisdisclosure provides a process for preparation of a compound of formulaI:

or a salt thereof;comprising contacting a compound of formula IV:

or a salt thereof;with a compound of formula V:

or a salt thereof,under reductive amination conditions to provide the compound of formulaI or a salt thereof.

In another embodiment, this disclosure provides a process forpreparation of a compound of formula I:

or a salt thereof, comprising:a) contacting a compound of formula A or a salt thereof, with a compoundof formula B or a salt thereof:

under addition conditions to provide a compound of formula III:

or a salt thereof;b) subjecting the compound of formula III or a salt thereof, toN-deprotection and alcohol reduction conditions to provide a compound offormula IV:

or a salt thereof; andc) contacting the compound of formula IV or a salt thereof with acompound of formula V:

or a salt thereof,under reductive amination conditions to provide the compound of formulaI or a salt thereof, wherein each PG independently is a protectinggroup.

In another embodiment, this disclosure provides a process forpreparation of a compound of formula II, named[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amineHCl salt:

comprising:a) contacting a compound of formula A or a salt thereof, with a compoundof formula B or a salt thereof:

under addition conditions to provide a compound of formula III:

or a salt thereof;b) subjecting the compound of formula III or a salt thereof, toN-deprotection and alcohol reduction conditions to provide a compound offormula IV:

or a salt thereof;c) contacting the compound of formula IV or a salt thereof with acompound of formula V:

or a salt thereof,under reductive amination conditions to provide the compound of formulaI:

andd) reacting the compound of formula I with HCl to provide the compoundof formula II, wherein each PG independently is a protecting group.

In another embodiment, this disclosure provides a compound of formulaIII:

or a salt thereof, wherein each PG independently is a protecting group.

In another embodiment, this disclosure provides a compound of formulaIIIa:

or a salt thereof.

In another embodiment, this disclosure provides a compound of formulaIV:

or a salt thereof.

More specific embodiments are described below.

DETAILED DESCRIPTION

Definitions

As used herein the following definitions apply unless clearly indicatedotherwise.

All atoms designated within a formula described herein, either within astructure provided, or within the definitions of variables related tothe structure, is intended to include any isotope thereof, unlessclearly indicated to the contrary. It is understood that for any givenatom, the isotopes may be present essentially in ratios according totheir natural occurrence, or one or more particular atoms may beenhanced with respect to one or more isotopes using synthetic methodsknown to one skilled in the art. Thus, hydrogen includes for example ¹H,²H, ³H; carbon includes for example ¹¹C, ¹²C, ¹³C, ¹⁴C; oxygen includesfor example ¹⁶O, ¹⁷O ¹⁸O; nitrogen includes for example ¹³N, ¹⁴N, ¹⁵N;sulfur includes for example ³²S, ³³S, ³⁴S, ³⁵S, ³⁶S, ³⁷S, ³⁸S; fluoroincludes for example ¹⁷F, ¹⁸F, ¹⁹F; chloro includes for example ³⁵Cl,³⁶Cl, ³⁷Cl, ³⁸Cl, ³⁹Cl; and the like.

Certain compounds contemplated for use in accordance with the presentdisclosure can exist in unsolvated forms as well as solvated forms,including hydrated forms. “Hydrate” refers to a complex formed bycombination of water molecules with molecules or ions of the solute.“Solvate” refers to a complex formed by combination of solvent moleculeswith molecules or ions of the solute. The solvent can be an organiccompound, an inorganic compound, or a mixture of both. Solvate is meantto include hydrate, hemi-hydrate, channel hydrate etc. Some examples ofsolvents include, but are not limited to, methanol,N,N-dimethylformamide, tetrahydrofuran, dimethylsulfoxide, and water. Ingeneral, the solvated forms are equivalent to unsolvated forms and areencompassed within the scope of the present disclosure. Certaincompounds contemplated for use in accordance with the present disclosuremay exist in multiple crystalline or amorphous forms. In general, allphysical forms are equivalent for the uses contemplated by the presentdisclosure and are intended to be within the scope of the presentdisclosure.

As used herein, the term “salt” refers to acid addition salts and basicaddition salts. Examples acid addition salts include those containingsulfate, chloride, hydrochloride, fumarate, maleate, phosphate,sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate,ethanesulfonate, benzenesulfonate, p-toluenesulfonate,cyclohexylsulfamate and quinate. Salts can be obtained from acids suchas hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid,sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid,malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonicacid, p-toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid, andquinic acid. Basic addition salts include those containing benzathine,chloroprocaine, choline, diethanolamine, ethanolamine, t-butylamine,ethylenediamine, meglumine, procaine, aluminum, calcium, lithium,magnesium, potassium, sodium, ammonium, alkylamine, and zinc, whenacidic functional groups, such as carboxylic acid or phenol are present.For example, see Remington's Pharmaceutical Sciences, 19^(th) ed., MackPublishing Co., Easton, Pa., Vol. 2, p. 1457, 1995. Such salts can beprepared using the appropriate corresponding bases.

The term “USP water” means water is the subject of an official monographin the current US Pharmacopeia.

Compounds can be formulated as or be in the form of a salt, includingpharmaceutically acceptable salts. Contemplated salt forms include,without limitation, mono, bis, tris, tetrakis, and so on. The term“pharmaceutically acceptable” indicates that the indicated material doesnot have properties that would cause a reasonably prudent medicalpractitioner to avoid administration of the material to a patient,taking into consideration the disease or conditions to be treated andthe respective route of administration. For example, it is commonlyrequired that such a material be essentially sterile, e.g., forinjectibles.

Pharmaceutically acceptable salts can be prepared by standardtechniques. For example, the free-base form of a compound can bedissolved in a suitable solvent, such as an aqueous or aqueous-alcoholsolution containing the appropriate acid and then isolated byevaporating the solution. In another example, a salt can be prepared byreacting the free base and acid in an organic solvent.

Thus, for example, if the particular compound is a base, the desiredpharmaceutically acceptable salt may be prepared by any suitable methodavailable in the art, for example, treatment of the free base with aninorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuricacid, nitric acid, phosphoric acid, and the like, or with an organicacid, such as acetic acid, maleic acid, succinic acid, mandelic acid,fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid,salicylic acid, a pyranosidyl acid, such as glucuronic acid orgalacturonic acid, an alpha-hydroxy acid, such as citric acid ortartaric acid, an amino acid, such as aspartic acid or glutamic acid, anaromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid,such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.

Similarly, if the particular compound is an acid, the desiredpharmaceutically acceptable salt may be prepared by any suitable method,for example, treatment of the free acid with an inorganic or organicbase, such as an amine (primary, secondary or tertiary), an alkali metalhydroxide or alkaline earth metal hydroxide, or the like. Illustrativeexamples of suitable salts include organic salts derived from aminoacids, such as L-glycine, L-lysine, and L-arginine, ammonia, primary,secondary, and tertiary amines, and cyclic amines, such ashydroxyethylpyrrolidine, piperidine, morpholine or piperazine, andinorganic salts derived from sodium, calcium, potassium, magnesium,manganese, iron, copper, zinc, aluminum and lithium.

The pharmaceutically acceptable salt of the different compounds may bepresent as a complex. Examples of complexes include 8-chlorotheophyllinecomplex (analogous to, e.g., dimenhydrinate: diphenhydramine8-chlorotheophylline (1:1) complex; Dramamine) and various cyclodextrininclusion complexes.

Unless specified to the contrary, specification of a compound hereinincludes pharmaceutically acceptable salts of such compound.

As used herein, the term “addition conditions” refers to the reactionconditions under which an aryl halide adds to an aryl aldehyde. The“addition conditions” as disclosed herein typically comprise a base anda catalyst. The non-limiting examples of the base include sodiumcarbonate, sodium bicarbonate, potassium carbonate, potassiumbicarbonate, potassium-tert-butoxide, potassium tert-pentoxide, cesiumcarbonate, lithium-tert-butoxide, magnesium-tert-butoxide,sodium-tert-butoxide, potassium hydroxide, lithium hydroxide and thelike. The addition conditions typically comprise a temperature rangingfrom about 0° C. to about −10° C. and reaction time of about 24 hours.The non-limiting examples of the catalyst include tetrabutylammoniumhydrogen sulfate, tetrabutylammonium fluoride, tetrabutylammoniumchloride, tetrabutylammonium bromide, tetrabutylammonium iodide,18-crown-6 and 15-crown-5.

As used herein, the term “reductive amination conditions” refers to thereaction conditions under which a carbonyl group is converted to anamine via reduction of the intermediate imine. The imine formation andreduction occur sequentially in one pot. “Reductive aminationconditions” as disclosed herein typically comprise triethylsilane andtrifluoroacetic acid. The reductive amination conditions typicallyfurther comprise addition of trifluoroacetic acid at a temperatureranging from about 0° C. to about −10° C. followed by stirring for about6 hours followed by addition of triethylsilane and refluxing for about24 hours. The non-limiting examples of reductive amination conditionsinclude sodium borohydride and benzoic acid; sodiumtriacetoxyborohydride and acetic acid; and the like.

As used herein, the term “protecting group” refers to a moiety of acompound that masks or alters the properties of a functional group orthe properties of the compound as a whole. The chemical substructure ofa protecting group varies widely. One function of a protective group isto serve as an intermediate in the synthesis of the parental drugsubstance. Chemical protecting groups and strategies forprotection/deprotection are well known in the art. See: “ProtectiveGroups in Organic Chemistry”, Theodora W. Greene (John Wiley & Sons,Inc., New York, 1991. Protecting groups are often utilized to mask thereactivity of certain functional groups, to assist in the efficiency ofdesired chemical reactions, e.g., making and breaking chemical bonds inan ordered and planned fashion. Protection of functional groups of acompound alters other physical properties besides the reactivity of theprotected functional group, such as the polarity, lipophilicity(hydrophobicity), and other properties which can be measured by commonanalytical tools. Chemically protected intermediates may themselves bebiologically active or inactive. The non-limiting examples of protectinggroups for an amine include t-butyloxycarbonyl (Boc), benzyloxycarbonyl(Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), and the like.

As used herein, the term “N-deprotection and alcohol reductionconditions” refers to the reaction conditions under which a protectinggroup from an amine is removed and a CH(OH) group is reduced to a CH₂group. These two transformations can be done in one step or two separatesteps, namely, “N-deprotection conditions” and “alcohol reductionconditions.” “N-deprotection and alcohol reduction conditions” asdisclosed herein, when done in one step, typically comprisetriethylsilane and trifluoroacetic acid. The N-deprotection and alcoholreduction conditions typically further comprise addition of atriorganosilane such as triethylsilane and trifluoroacetic acid at aninitial temperature of about 0-10° C. followed stirring for about 24hours at room temperature followed by refluxing for about 8 hours.

As used herein, the term “N-deprotection conditions” refers to thereaction conditions under which a protecting group from an amine isremoved. The non-limiting examples of protective groups for an amineinclude tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz),9-fluorenylmethoxycarbonyl (Fmoc), and the like. The N-deprotectionconditions for Boc include using an acid such as HCl, methanesulfonicacid, para-toluenesulfonic acid, and the like. The N-deprotectionconditions for Cbz include hydrogenation using hydrogen and a catalystsuch as Pd and the like. The N-deprotection conditions for Fmoc includeusing a base such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),piperidine, and the like.

As used herein, the term “alcohol reduction conditions” refers to thereaction conditions under which a CH(OH) group is reduced to a CH₂group. The “alcohol reduction conditions” include chlorodipohenylsilanewith InCl₃; triethylsilane and a catalyst; and the like.

In addition, abbreviations as used herein have respective meanings asfollows:

br broad D doublet DMSO dimethylsulfoxide Eq equivalent gm gram HPLChigh pressure liquid chromatography kg kilogram L liter mL milliliterMTBE methyl t-butyl ether NMR nuclear magnetic resonance S singlet TFAtrifluoroacetic acid vol volumeProcess

As described generally above, the disclosure provides in someembodiments a process for making a compound of formula I. In anotherembodiment, the disclosure provides processes for making intermediatesfor the compound of formula I.

The present disclosure provides in one embodiment a process for making acompound of formula I, named[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine:

or a salt thereof.

In another embodiment, this disclosure provides a process forpreparation of a compound of formula I, named[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine:

or a salt thereof, comprising:a) contacting a compound of formula A or a salt thereof, with a compoundof formula B or a salt thereof:

under addition conditions to provide a compound of formula III:

or a salt thereof;b) subjecting the compound of formula III or a salt thereof, toN-deprotection and alcohol reduction conditions to provide a compound offormula IV:

or a salt thereof; andc) contacting the compound of formula IV or a salt thereof with acompound of formula V:

or a salt thereof,under reductive amination conditions to provide the compound of formulaI or a salt thereof, wherein each PG independently is a protectinggroup.

The addition conditions of step a) comprise a base and a catalyst. Thenon-limiting examples of the base include sodium carbonate, sodiumbicarbonate, potassium carbonate, potassium bicarbonate,potassium-tert-butoxide, potassium tert-pentoxide, cesium carbonate,lithium-tert-butoxide, magnesium-tert-butoxide, sodium-tert-butoxide,potassium hydroxide and lithium hydroxide. The non-limiting examples ofthe catalyst include tetrabutylammonium hydrogen sulfate,tetrabutylammonium fluoride, tetrabutylammonium chloride,tetrabutylammonium bromide, tetrabutylammonium iodide, 18-crown-6 and15-crown-5.

The addition conditions of step a) further comprise a solvent. Thenon-limiting examples of the solvent include isopropyl alcohol, toluene,acetonitrile, nitromethane, N,N-dimethylformamide,N,N-dimethylacetamide, dimethylsulfoxide, 3-methyl-1-butanol,2-methoxyethanol, 2-propanol, and xylene.

The addition conditions of step a) further comprise a temperature ofabout 15-25° C.

A variety of protecting groups, PG, can be used in compound of formulaA. The non-limiting examples of protecting groups for amines includet-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz),9-fluorenylmethoxycarbonyl (Fmoc), and the like. In one embodiment, PGis Boc. The N-deprotection conditions of step b) refer to conditionsunder which the protective group, P, is removed. In one embodiment, PGis Boc and the N-deprotecting conditions comprise an acid such as HCl,methanesulfonic acid, toluenesulfonic acids, and the like. In oneembodiment, the acid is para-toluenesulfonic acid.

The N-deprotection and alcohol reduction conditions of step b) comprisetriethylsilane and trifluoroacetic acid.

The N-deprotection and alcohol reduction conditions of step b) furthercomprise a solvent. The non-limiting examples of the solvent includeacetonitrile, 1,2-dichloroethane, dichloromethane, tetrahydrofuran,1,2-dimethoxyethane, butyl acetate, acetone, 2-butanone, anddimethylsulfoxide.

The reductive amination conditions of step c) comprise triethylsilaneand trifluoroacetic acid.

The reductive amination conditions of step c) further comprise asolvent. The non-limiting examples of the solvent include acetonitrile,1,2-dichloroethane, dichloromethane, tetrahydrofuran,1,2-dimethoxyethane, butyl acetate, acetone, acetonitrile, 2-butanone,and dimethylsulfoxide.

In another embodiment, this disclosure provides a process forpreparation of a compound of formula compound of formula II:

comprising:a) contacting a compound of formula A or a salt thereof, with a compoundof formula B or a salt thereof:

under addition conditions to provide a compound of formula III:

or a salt thereof;b) subjecting the compound of formula III or a salt thereof, toN-deprotection and alcohol reduction conditions to provide a compound offormula IV:

or a salt thereof;c) contacting the compound of formula IV or a salt thereof with acompound of formula V:

or a salt thereof,under reductive amination conditions to provide the compound of formulaI:

andd) reacting the compound of formula I with HCl to provide the compoundof formula II wherein each PG independently is a protecting group.

The addition conditions of step a) comprise a base and a catalyst. Thenon-limiting examples of the base include sodium carbonate, sodiumbicarbonate, potassium carbonate, potassium bicarbonate,potassium-tert-butoxide, potassium tert-pentoxide, cesium carbonate,lithium-tert-butoxide, magnesium-tert-butoxide, sodium-tert-butoxide,potassium hydroxide and lithium hydroxide. The non-limiting examples ofthe catalyst include tetrabutylammonium hydrogen sulfate,tetrabutylammonium fluoride, tetrabutylammonium chloride,tetrabutylammonium bromide, tetrabutylammonium iodide, 18-crown-6 and15-crown-5.

The addition conditions of step a) further comprise a solvent. Thenon-limiting examples of the solvent include isopropyl alcohol, toluene,acetonitrile, nitromethane, N,N-dimethylformamide,N,N-dimethylacetamide, dimethylsulfoxide, 3-methyl-1-butanol,2-methoxyethanol, 2-propanol, and xylene.

The addition conditions of step a) further comprise a temperature ofabout 15-25° C.

A variety of protecting groups, PG, can be used in compound of formulaA. The non-limiting examples of protecting groups for amines includet-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz),9-fluorenylmethoxycarbonyl (Fmoc), and the like. In one embodiment, PGis Boc. The N-deprotection conditions of step b) refer to conditionsunder which the protective group, P, is removed. In one embodiment, PGis Boc and the N-deprotecting conditions comprise an acid such as HCl,methanesulfonic acid, toluenesulfonic acids, and the like. In oneembodiment, the acid is para-toluenesulfonic acid.

The N-deprotection and alcohol reduction conditions of step b) comprisetriethylsilane and trifluoroacetic acid.

The N-deprotection and alcohol reduction conditions of step b) furthercomprise a solvent. Non-limiting examples of the solvent includeacetonitrile, 1,2-dichloroethane, dichloromethane, tetrahydrofuran,1,2-dimethoxyethane, butyl acetate, acetone, 2-butanone, anddimethylsulfoxide.

The reductive amination conditions of step c) comprise triethylsilaneand trifluoroacetic acid.

The reductive amination conditions of step c) further comprise asolvent. The non-limiting examples of the solvent include acetonitrile,1,2-dichloroethane, dichloromethane, tetrahydrofuran,1,2-dimethoxyethane, butyl acetate, acetone, acetonitrile, 2-butanone,and dimethylsulfoxide.

In another embodiment, this disclosure provides a process forpreparation of a compound of formula III:

or a salt thereof;comprising contacting a compound of formula A or a salt thereof, with acompound of formula B or a salt thereof:

under addition conditions to provide the compound of formula III or asalt thereof, wherein each PG independently is a protecting group.

The addition conditions comprise a base and a catalyst. The non-limitingexamples of the base include sodium carbonate, sodium bicarbonate,potassium carbonate, potassium bicarbonate, potassium-tert-butoxide,potassium tert-pentoxide, cesium carbonate, lithium-tert-butoxide,magnesium-tert-butoxide, sodium-tert-butoxide, potassium hydroxide andlithium hydroxide. The non-limiting examples of the catalyst includetetrabutylammonium hydrogen sulfate, tetrabutylammonium fluoride,tetrabutylammonium chloride, tetrabutylammonium bromide,tetrabutylammonium iodide, 18-crown-6 and 15-crown-5.

The addition conditions further comprise a solvent. The non-limitingexamples of the solvent include isopropyl alcohol, toluene,acetonitrile, nitromethane, N,N-dimethylformamide,N,N-dimethylacetamide, dimethylsulfoxide, 3-methyl-1-butanol, 2-methoxyethanol, 2-propanol, and xylene.

The addition conditions further comprise a temperature of about 15-25°C.

A variety of protecting groups, PG, can be used in compound of formulaA. The non-limiting examples of protecting groups for amines includet-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz),9-fluorenylmethoxycarbonyl (Fmoc), and the like. In one embodiment, PGis Boc.

In another embodiment, this disclosure provides a process forpreparation of a compound of formula IV:

or a salt thereof;comprising subjecting a compound of formula III:

or a salt thereof, to N-deprotection and alcohol reduction conditions toprovide the compound of formula IV or a salt thereof, wherein each PGindependently is a protecting group.

A variety of protecting groups, PG, can be used in compound of formulaIII. The non-limiting examples of protecting groups for amines includet-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz),9-fluorenylmethoxycarbonyl (Fmoc), and the like. In one embodiment, PGis Boc.

The N-deprotection and alcohol reduction conditions of step b) comprisetriethylsilane and trifluoroacetic acid.

The N-deprotection and alcohol reduction conditions further comprise asolvent. The non-limiting examples of the solvent include acetonitrile,1,2-dichloroethane, dichloromethane, tetrahydrofuran,1,2-dimethoxyethane, butyl acetate, acetone, 2-butanone, anddimethylsulfoxide.

In another embodiment, this disclosure provides a process forpreparation of a compound of formula I:

or a salt thereof;comprising contacting a compound of formula IV:

or a salt thereof;with a compound of formula V:

or a salt thereof,under reductive amination conditions to provide the compound of formulaI or a salt thereof.

The reductive amination conditions comprise triethylsilane andtrifluoroacetic acid.

The reductive amination conditions further comprise a solvent. Thenon-limiting examples of the solvent include acetonitrile,1,2-dichloroethane, dichloromethane, tetrahydrofuran,1,2-dimethoxyethane, butyl acetate, acetone, acetonitrile, 2-butanone,and dimethylsulfoxide.

Compounds

In another embodiment, this disclosure provides a compound of formulaIII:

or a salt thereof, wherein each PG independently is a protecting group.

A variety of protecting groups, PG, can be used in compound of formulaA. The non-limiting examples of protecting groups for amines includet-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz),9-fluorenylmethoxycarbonyl (Fmoc), and the like. In one embodiment, PGis Boc.

In another embodiment, this disclosure provides a compound of formulaIV:

or a salt thereof.

In another embodiment, the salt of the compound of formula IV is atrifluoroacetic acid salt.

The intermediates in the process for the synthesis of formula I can beused in the next step with or without purification. The conventionalmeans of purification include recrystallization, chromatography (e.g.adsorbant, ion exchange, and HPLC), and the like.

EXAMPLES

The compounds of the disclosure may be prepared using methods disclosedherein and routine modifications thereof which will be apparent giventhe disclosure herein and methods well known in the art. Conventionaland well-known synthetic methods may be used in addition to theteachings herein. The synthesis of compounds described herein, may beaccomplished as described in the following examples. If available,reagents may be purchased commercially, e.g. from Sigma Aldrich or otherchemical suppliers. Unless otherwise noted, the starting materials forthe following reactions may be obtained from commercial sources.

Examples related to the present invention are described below. In mostcases, alternative techniques can be used. The examples are intended tobe illustrative and are not limiting or restrictive to the scope of theinvention.

Example 1. Synthesis of[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine

Step 1: Conversion of A to IIIa

The reactor was charged with Compound A (1000 gm, 1.0 eq.), Compound B(497 gm, 1.05 eq.), tetrabutylammonium hydrogen sulfate (31.6 gm, 0.03eq.) and isopropanol (12 L, 11.8 vol). The reaction mixture was stirredfor at least about an hour to obtain a near clear, yellow solution. Thenpotassium tert-pentoxide (73 mL, 0.04 eq.) was added over 30 seconds.The reaction mixture was stirred at about 15-25° C. for about 20-24hours. The reaction was monitored by HPLC. When the content of compoundIIIa was more than 80%, the reaction was deemed complete. The reactionmixture was cooled to about 0-10° C. and then stirred for at least about2 hours. The precipitate was filtered, washed with 3 L isopropanol thathad been cooled to 0° C. and dried to provide compound IIIa as a whitesolid (1.34 kg, 91.2% yield, 97.7% purity by HPLC). ¹H NMR (DMSO-d6): δ(ppm) 11.8 (s, NH), 8.50-8.51 (d, 1H), 8.17 (d, 1H), 7.85-7.88 (dd, 1H),7.82 (d, 1H), 7.41 (S, 1H), 7.29-7.31 (d, 1H), 6.04 (s, 2H), and 1.35(s, 18H).

Alternatively, potassium tert-pentoxide can also be used in thisreaction as a 25% solution in toluene.

Step 2: Conversion of IIIa to IV

The reactor was charged with compound IIIa (1.1 kg, 1 eq.) andacetonitrile (8.8 L, 12.4 vol) and the reaction mixture was stirred.Then triethylsilane (1.35 kg, 5 eq.) was added at about 15-30° C. overat least about 10 minutes. Then trifluoroacetic acid (2.38 kg, 9 eq.)was added to the reactor at about 15-30° C. over at least about 30minutes. The reaction mixture was heated at about 55-65° C. over atleast about 4 hours. It was then stirred at about 55-65° C. for about20-48 hours. The reaction was monitored by HPLC. When the content ofcompound IIIa was less than about 1%, the reaction was deemed complete.The reaction mixture was cooled to about 45-55° C. and then a)concentrated to 3.3 L under vacuum and b) water (8.25 L) was charged.Steps a) and b) were repeated 4 times. The reaction mixture was thenheated at about 45-60° C. and stirred for bout 1-3 hours. It was thencooled to about 0-10° C. over at least about 2 hours and it was stirredat about 0-10° C. for about 2-4 hours. The precipitate was filtered,washed with 2.2 L water and then with heptane (1.1 L) and dried toprovide the TFA salt of compound IV as an off-white solid (673.3 gm,77.9% yield, 99.7% purity by HPLC). ¹H NMR (DMSO-d6): δ (ppm) 11.78 (s,COOH), 8.18 (d, 1H), 8.08-8.09 (broad doublet, 2H), 7.93-7.94 (d, 1H),7.81-7.84 (dd, 1H), 7.47-7.48 (d, 1H), 6.90-6.93 (d, 1H), 3.92 (s, 2H).

Step 3: Conversion of IV to I

The reactor was charged with compound IV (663.3 gm, 1 eq.), compound V(623.2 gm, 2.0 eq.) and acetonitrile (13.3 L). The reaction mixture wasstirred for about 5-10 minutes at room temperature. Triethylsilane(1531.6 gm, 7.4 eq.) was then added to the reactor over at least about10 minutes at or less than about 30° C. Trifluoroacetic acid (1542.5 gm,7.6 eq.) was added to the reactor over at least about 10 minutes at orless than about 30° C. The reaction mixture was stirred for at leastabout 30 minutes at about 15-30° C. It was then heated to about 70-82°C. over at least about one hour and then stirred at about 70-82° C. forabout 20-48 hours. The reaction was monitored by HPLC. When the contentof compound IV was less than about 1%, the reaction was deemed complete.

The reaction mixture was cooled to room temperature, the acetonitrilelayer was separated and concentrated. Then water (7.96 L) was chargedand the reaction mixture was concentrated to 6.64 L under vacuumproviding a tri-phasic mixture. It was then cooled to 15-25° C., chargedwith ethyl acetate (10.6 L) and stirred providing a biphasic mixture. Itwas cooled to 0-10° C., charged with a 25% NaOH solution in water untila pH of about 8-9 was reached with vigorous stirring, heated to about65-75° C. and stirred at about 65-75° for about 30 minutes. The organiclayer was separated, and water (3.98 L) was charged and the reactionmixture was heated at about 65-75° C. The organic layer was separatedand concentrated to about 5.3-5.9 L under vacuum, heptane (11.9 L) wasadded and the slurry was heated to about 55-65° C. and stirred for about2 hours. The reaction mixture was cooled to about 15-30° C. over atleast about 2 hours and then stirred at about 15-30° C. for at leastabout 1 hour. The precipitate was filtered, washed with heptane (1.99 L)and dried. The filter cake was charged into reactor with ethyl acetate(5.31 L, 8 vol) and heptane (2.65 L, 4 vol), cooled to about 15-30° C.over at least about 2 hours and then stirred at about 15-30° C. for atleast about 1 hour. The precipitate was filtered, washed with heptaneand dried to provide Compound I as a light yellow solid (648.4 gm, 89.4%yield, 99.4% purity by HPLC).

Step 4: Conversion of I to II

The reactor was charged with compound I (10 gm, 1 eq.), 110 mL ethanolwas added and the reaction mixture was stirred. Concentratedhydrochloric acid (4.7 gm, 2 eq.) was slowly added to the reactionmixture while maintaining a temperature of about 30° C. or less to forma clear solution. It was then filtered and washed with methanol (10 mL).It was again filtered and purified water (3 mL) was added to it at about28-32° C. The mixture was stirred at about 28-32° C. for 1-3 hours andfiltered, purified water (177 mL) was added to it at about 25-32° C. Thereaction mixture was cooled at about 0-7° C. and stirred for at leastabout 2 hours. Optionally, seed crystals of compound II can be added inthis step. The solids were filtered, rinsed with a cool (0-5° C.)mixture of methanol (6 mL) and MTBE (24 mL), and with cool (0-5° C.)MTBE (30 mL). The product was dried to provide Compound II (90% yield).

The crystallization of Compound II to Form C was carried out using (A)0.5.% volume/volume wet methyl tert-butyl ether (MTBE); (B) 1.0.%volume/volume wet MTBE; and (C) 1.5% volume/volume wet MTBE as describedbelow. Form C, which was made by either crystallization procedure (A),(B) or (C) described below, was characterized by an X-ray powderdiffractogram (XRPD) comprising peaks)(±0.2° at 7.1, 16.5, 20.8, 23.2and 28.1 °2θ as determined on a diffractometer using Cu-Ka radiation.These peaks are consistent with the XRPD peaks of Form C that aredescribed in U.S. Ser. No. 62/157,902)(±0.2°, filed on May 6, 2015,which is incorporated herein by reference in its entirety.

Procedure (A): Preparation of 0.5% Volume/Volume Wet MTBE (1000 mL):

-   (1) 5 mL of USP water was charged to 1000 mL volumetric flask and    diluted with 1000 mL of MTBE. The resulting solution was stirred for    about 30 minutes.-   (2) A 500 mL 3 neck flask equipped with an overhead stirrer,    nitrogen inlet, and condenser was charged with mechanically sieved    Compound II. Compound II was mechanically sieved with a sieving    machine.-   (3) The reaction mixture was diluted with 0.5% v/v wet MTBE (300 mL,    15 vol) and stirred.-   (4) The reaction mixture was slowly heated to reflux temperature    (52-53° C.) and reflux was continued for about 24 hours. Agitation    speed was increased as the reaction mixture thickened.-   (5) Samples were pulled at 1 hour, 2 hours, 4 hours, 8 hours, 12    hours and 24 hours.-   (6) The reaction mixture was cooled to room temperature and stirred    for about 6 hours.-   (7) The reaction mixture was filtered and the cake was washed the    cake with MTBE (2 vol, 40 mL).-   (8) The resulting product was dried at 40-45° C. overnight.-   (9) The crystallized product was determined to be Form C by XRPD.    Procedure (B): Preparation of 1.0% Volume/Volume Wet MTBE (1000 mL):-   (1) 10 mL of USP water was charged to 1000 mL volumetric flask and    diluted with 1000 mL of MTBE. The resulting solution was stirred for    about 60 minutes.-   (2) A 500 mL 3 neck flask equipped with an overhead stirrer,    nitrogen inlet, and condenser was charged with mechanically sieved    Compound II. Compound II was mechanically sieved with a sieving    maching.-   (3) The reaction mixture was diluted with 1.0% v/v wet MTBE (300 mL,    15 vol) and stirred.-   (4) The reaction mixture was slowly heated to reflux temperature    (52-53° C.) and reflux was continued for about 24 hours. Agitation    speed was increased as the reaction mixture thickened.-   (5) Samples were pulled at 1 hour, 2 hours, 4 hours, 8 hours, 12    hours and 24 hours.-   (6) The reaction mixture was cooled to room temperature and stirred    for about 6 hours.-   (7) The reaction mixture was filtered and the cake was washed the    cake with MTBE (2 vol, 40 mL).-   (8) The resulting product was dried at 40-45° C. overnight.-   (9) The crystallized product was determined to be Form C by XRPD.    Procedure (C): Preparation of 1.0% Volume/Volume Wet MTBE (1000 mL):-   (1) 15 mL of USP water was charged to 1000 mL volumetric flask and    diluted with 1000 mL of MTBE. The resulting solution was stirred for    about 60 minutes.-   (2) A 500 mL 3 neck flask equipped with an overhead stirrer,    nitrogen inlet, and condenser was charged with micronized compound    II mechanically sieved Compound II. Compound II was mechanically    sieved with a sieving maching.-   (3) The reaction mixture was diluted with 1.0% v/v wet MTBE (300 mL,    15 vol) and stirred.-   (4) The reaction mixture was slowly heated to reflux temperature    (52-53° C.) and reflux was continued for about 24 hours. Agitation    speed was increased as the reaction mixture thickened.-   (5) Samples were pulled at 1 hour, 2 hours, 4 hours, 8 hours, 12    hours and 24 hours.-   (6) The reaction mixture was cooled to room temperature and stirred    for about 6 hours.-   (7) The reaction mixture was filtered and the cake was washed the    cake with MTBE (2 vol, 40 mL).-   (8) The resulting product was dried at 40-45° C. overnight.-   (9) The crystallized product was determined to be Form C by XRPD.

Another embodiment of this disclosure relates to process of preparingcrystalline Form C of Compound II:

comprising:

(1) adding Compound II to from about 0.4% v/v wet MTBE to about 1.5% v/vwet MTBE to provide a reaction mixture;

(2) refluxing the reaction mixture;

(3) cooling the reaction mixture to about room temperature; and

(4) isolating the crystalline Form C of Compound II from the reactionmixture.

For step (1), it will be understood that either Compound II can be addedto wet MTEB, or wet MTEB can be added to Compound II.

In another embodiment of the of process of preparing crystalline Form Cof Compound II, step (1) comprises adding Compound II to about 0.5% v/vwet MTBE to provide a reaction mixture.

In another embodiment of the of process of preparing crystalline Form Cof Compound II, step (2) further comprises heating the reaction mixtureto a temperature of about 52-53° C.

Another embodiment of this disclosure relates to a process of preparingcrystalline Form C of Compound II, comprising the steps of:

(a) adding MTBE to USP water and optionally stirring, mixing oragitating the reaction mixture;

(b) diluting mechanically sieved Compound II with from about 0.4% v/vwet MTBE to about 1.5% v/v wet MTBE, and optionally stirring, mixing oragitating the reaction mixture;

(c) refluxing the reaction mixture, and optionally increasing theagitation, stirring or mixing;

(d) cooling the reaction mixture to about room temperature; and

(e) isolating the cake from the reaction mixture and washing the cakewith MTBE.

In another embodiment of the process of preparing crystalline Form C ofCompound II, Compound II in step (a) is mechanically sieved with asieving machine.

It will be understood that in step (a), Compound II can be added to wetMTBE, or wet MTBE can be added to Compound II.

In another embodiment of the process of preparing crystalline Form C ofCompound II, step (b) comprises diluting mechanically sieved Compound IIwith about 0.5% v/v wet MTBE, and stirring, mixing or agitating thereaction mixture.

In another embodiment of the process of preparing crystalline Form C ofCompound II, step (b) comprises diluting mechanically sieved Compound IIwith about 0.6% v/v wet MTBE, and stirring, mixing or agitating thereaction mixture.

In another embodiment of the process of preparing crystalline Form C ofCompound II, step (b) comprises diluting mechanically sieved Compound IIwith about 0.7% v/v wet MTBE, and stirring, mixing or agitating thereaction mixture.

In another embodiment of the process of preparing crystalline Form C ofCompound II, step (b) comprises diluting mechanically sieved Compound IIwith about 0.8% v/v wet MTBE, and stirring, mixing or agitating thereaction mixture.

In another embodiment of the process of preparing crystalline Form C ofCompound II, step (b) comprises diluting mechanically sieved Compound IIwith about 0.9% v/v wet MTBE, and stirring, mixing or agitating thereaction mixture.

In another embodiment of the process of preparing crystalline Form ofCompound II, step (b) comprises diluting mechanically sieved Compound IIwith about 1.0% v/v wet MTBE, and stirring, mixing or agitating thereaction mixture.

In another embodiment of the process of preparing crystalline Form C ofCompound II, step (c) comprises heating the reaction mixture to a refluxtemperature of about 50-56° C. and refluxing.

In another embodiment of the process of preparing crystalline Form C ofCompound II, step (c) comprises heating the reaction mixture to a refluxtemperature of about 52-53° C. and refluxing.

In another embodiment of the process of preparing crystalline Form C ofCompound II, step (c) comprises heating reaction mixture to a refluxtemperature of about 52-53° C., and refluxing for about 24 hours.

In another embodiment of the process of preparing crystalline Form C ofCompound II, step (d) comprises cooling the reaction mixture to aboutroom temperature and stirring the reaction mixture for about 4-8 hours.

In another embodiment of the process of preparing crystalline Form C ofCompound II, step (d) comprises isolating the cake from the reactionmixture and washing the cake with MTBE.

In another embodiment of the process of preparing crystalline Form C ofCompound II, the resulting product from step (e) is dried.

In another embodiment of the process of preparing crystalline Form C ofCompound II, the resulting product from step (e) is dried at about35-50° C. overnight.

In another embodiment of the process of preparing crystalline Form C ofCompound II, the resulting product from step (e) is dried at about40-45° C. overnight.

In another embodiment of the process of preparing crystalline Form C ofCompound II, the crystalline Form C that is obtained from step (4) orstep (e) is characterized by an X-ray powder diffractogram (XRPD)comprising peaks (±0.2°) at 7.1, 16.5, 20.8, 23.2 and 28.1 °2θ asdetermined on a diffractometer using Cu-Ka radiation.

All patents and other references cited in the specification areindicative of the level of skill of those skilled in the art to whichthe disclosure pertains, and are incorporated by reference in theirentireties, including any tables and figures, to the same extent as ifeach reference had been incorporated by reference in its entiretyindividually.

One skilled in the art would readily appreciate that the presentdisclosure is well adapted to obtain the ends and advantages mentioned,as well as those inherent therein. The methods, variances, andcompositions described herein as presently representative of preferredembodiments are exemplary and are not intended as limitations on thescope of the disclosure. Changes therein and other uses will occur tothose skilled in the art, which are encompassed within the spirit of thedisclosure, are defined by the scope of the claims.

The disclosure illustratively described herein suitably may be practicedin the absence of any element or elements, limitation or limitationswhich is not specifically disclosed herein. Thus, for example, in eachinstance herein any of the terms “comprising”, “consisting essentiallyof” and “consisting of” may be replaced with either of the other twoterms. Thus, for an embodiment of the disclosure using one of the terms,the disclosure also includes another embodiment wherein one of theseterms is replaced with another of these terms. In each embodiment, theterms have their established meaning. Thus, for example, one embodimentmay encompass a method “comprising” a series of steps, anotherembodiment would encompass a method “consisting essentially of” the samesteps, and a third embodiment would encompass a method “consisting of”the same steps. The terms and expressions which have been employed areused as terms of description and not of limitation, and there is nointention that in the use of such terms and expressions of excluding anyequivalents of the features shown and described or portions thereof, butit is recognized that various modifications are possible within thescope of the disclosure claimed. Thus, it should be understood thatalthough the present disclosure has been specifically disclosed bypreferred embodiments and optional features, modification and variationof the concepts herein disclosed may be resorted to by those skilled inthe art, and that such modifications and variations are considered to bewithin the scope of this disclosure as defined by the appended claims.

In addition, where features or aspects of the disclosure are describedin terms of Markush groups or other grouping of alternatives, thoseskilled in the art will recognize that the disclosure is also therebydescribed in terms of any individual member or subgroup of members ofthe Markush group or other group.

Also, unless indicated to the contrary, where various numerical valuesare provided for embodiments, additional embodiments are described bytaking any 2 different values as the endpoints of a range. Such rangesare also within the scope of the described disclosure.

Thus, additional embodiments are within the scope of the disclosure andwithin the following claims.

What is claimed is:
 1. A process of preparing a crystalline form ofCompound II:

comprising: (1) adding Compound II to from about 0.4% v/v wet methyltert-butyl ether (MTBE) to about 1.5% v/v wet MTBE to provide a reactionmixture; (2) refluxing the reaction mixture; (3) cooling the reactionmixture to about room temperature; and (4) isolating the crystallineform of Compound II from the reaction mixture.
 2. The process accordingto claim 1, wherein step (1) comprises adding Compound II to about 0.5%v/v wet methyl tert-butyl ether (MTBE) to provide the reaction mixture.3. The process according to claim 2, wherein step (2) further comprisesheating the reaction mixture to a temperature of about 52-53° C.
 4. Theprocess according to claim 3, wherein the crystalline form of compoundII is characterized by an X-ray powder diffractogram (XRPD) comprisingpeaks (±0.2°) at 7.1, 16.5, 20.8, 23.2 and 28.1 °2θ as determined on adiffractometer using Cu-Ka radiation.